Defining the mechanisms driving tau deposition and spread is a critical but poorly understood issue in Alzheimer's disease (AD) and Chronic Traumatic Encephalopathy (CTE). There is growing evidence that microvascular dysfunction and neuroinflammation occur early in both diseases and exacerbate tau pathology. Microvasculopathy, blood brain barrier (BBB) dysfunction and neuroinflammation are also consequences of exposure to repetitive head impacts (RHI) experienced during contact sports and military participation. CTE is characterized by the perivascular accumulation of tau and progressive decline in cognitive, behavioral and mood function; CTE is also associated with RHI exposure. Our preliminary studies suggest that the microvasculopathy and inflammation associated with CTE is distinctive from AD and that tau deposition is accelerated in CTE, resulting in neurofibrillary degeneration of the medial temporal lobe a decade earlier than in aging or AD. Identifying the molecular features driving tau pathology in CTE will provide important insights into mechanisms governing tau pathology in AD. Pinpointing the distinctions and commonalities in inflammation, microvasculopathy and BBB pathology between AD and CTE and determining their relationship to RHI will provide fundamental insights into the initiation and spread of tau pathology and the pathogenesis of tauopathies. Given that 15 million students participate in contact sports and 300,000 military veterans have been exposed to blast and concussive injury, there is great urgency to understanding the effects of RHI exposure on microvasculopathy, inflammation and the development of tau pathology in CTE and AD. In this application, we will use large, well-characterized, novel cohorts, including the largest neuropathologically confirmed autopsy cohort of subjects with CTE in the world (N=250), our AD brain bank (N=800), and controls from the VA and Framingham Heart Study, both exposed to RHI (N=40) and not exposed to RHI (N=80), and comprehensive clinical and pathological FITBIR-compliant datasets, to study the relationship between RHI exposure, tau pathology, microvasculopathy, neuroinflammation, A, ?-synuclein, and TDP-43 accumulation and clinical decline in CTE, AD, RHI-controls and non-RHI controls. We will also examine whether APOE?4 and MAPT status impact these relationships. Our long-term goal is to identify innovative biomarkers and targets for pharmacotherapy based on the distinctive microvascular and inflammatory profiles of AD and CTE. Most biomarkers for the detection of CTE and AD in living subjects have focused on tau, A, axonal, and astrocytic markers, yet vascular dysfunction is an early event in AD and CTE and heralds the onset of clinical symptoms. The proposed studies will expand potential biomarkers to include novel markers of vascular dysfunction, inflammation and accelerated tau pathology in the medial temporal lobe as suggested by our preliminary studies. This research has the potential to transform our conceptualization of neurodegeneration and identify key mechanisms driving tau deposition and spread in tauopathies.